The present invention relates to a series of new 13-substituted milbemycin 5-oxime derivatives which have valuable acaricidal, insecticidal and anthelmintic activities. The invention also provides methods and compositions for using these compounds as well as processes for their preparation.
There are several classes of known compounds with a structure based on a 16-membered macrolide ring, which are obtained by fermentation of various microorganisms or semi-synthetically by chemical derivatization of such natural fermentation products, and which exhibit acaricidal, insecticidal, anthelmintic and antiparasitic activities. The milbemycins and avermectins are examples of two such classes of known compounds, but others exist and are normally identified in the prior art by different names or code numbers. The namers for these various macrolide compounds have generally been taken from the names or code numbers of the microorganisms which produce the naturally occurring members of each class, and these names have then been extended to cover the chemical derivatives of the same class, with the result that there has been no standardized systematic nomenclature for such compounds generally.
In order to avoid confusion, a standardized system of nomenclature will be used herein, which follows the normal rules for naming derivatives of organic compounds as recommended by the International Union of Pure and Applied Chemistry (IUPAC), Organic Chemistry Division, Commission on Nomenclature of Organic Chemistry, and which is based on the hypothetical parent compound hereby defined as "milbemycin", which is that compound represented by the following formula (A): ##STR3## wherein R.sup.a and R.sup.b both represent hydrogen atoms.
For the avoidance of doubt, the above formula (A) also shows the numbering of positions of the macrolide ring system applied to those positions of most relevance to the compounds of the present invention.
The naturally produced inilbemycins are a series of macrolide compounds known to have anthelmintic, acaricidal and insecticidal activities. Milbemycin D was disclosed in U.S. Pat. No. 4,346,171, where it was referred to as"Compound B-41D", and milbemycins A.sub.3 and A.sub.4 were disclosed in U.S. Pat. No. 3,950,360. These compounds may be represented by the above formula (A) in which R.sup.a at position 13 is a hydrogen atom and R.sup.b at position 25 is a methyl group, an ethyl group or an isopropyl group, these compounds being designated as milbemycin A.sub.3, milbemycin A.sub.4 and milbemycin D, respectively. The milbemycin analog having a hydrogen atom at position 13 and substituted at position 25 with a sec-butyl group was disclosed in U.S. Pat. No. 4,173,571, where it was known as "13-deoxy-22,23-dihydroavermectin B.sub.1a aglycone".
Subsequently, various derivatives of the original milbemycins and avermectins have been prepared and their activities investigated. For example, 5-esterified milbemycins have been disclosed in U.S. Pat. No. 4,201,861, Pat. No. 4,206,205, Pat. No. 4,173,571, Pat. No. 4,171,314, Pat. No. 4,203,976, Pat. No. 4,289,760, Pat. No. 4,457,920, Pat. No. 4,579,864 and Pat. No. 4,547,491, in European Patent Publications No. 8184, No. 102,721, No. 115,930, No. 180,539 and No. 184,989 and in Japanese Patent Applications Kokai (i.e. as laid open to public inspection) No. 57-120589 and 59-16894.
13-Hydroxy-5-ketomilbemycin derivatives have been disclosed in U.S. Pat. No. 4,423,209. Milbemycin 5-oxime derivatives were disclosed in U.S. Pat. No. 4,547,520 and in European Patent Publication No. 203 832.
Milbemycins having an ester bond at the 13-position are of particular relevance to the present invention and a number of compounds in which the 13-hydroxy group in the compounds of the above formula (A) has been esterified is disclosed in Japanese Patent Kokai Application No. Sho 61-180787, which describes esters of a variety of carboxylic acids such as the alkanoic acids. Other milbemycin derivatives having an ester bond at the 13-position are described in Japanese Patent Kokai Application No. Hei 1-104078. In this document there are disclosed compounds in which the carboxylic acid moiety has a side chain, such as an alkyl group, at the .alpha.-position of the carboxylic acid group.
The closest prior art to the present invention is thought by us to be represented by U.S. Pat. No. 4,963,582 (equivalent to European Patent No. 246 739), which discloses a series of 13-ester derivatives. These, however, differ from the compounds of the present invention in the nature of the group at the 13-position.
The various classes of milbemycin-related macrolide compounds referred to above are all disclosed as having one or more types of activity as antibiotic, anthelmintic, ectoparasiticidal, acaricidal or other pesticidal agents. However, there is still a continuing need to provide such agents with improved activity against one or more classes of agricultural and horticultural pests.
It has now been discovered that the activity of such milbemycin-related derivatives can be improved by appropriately selecting the combination of substituents on the macrolide ring system, especially the substituents at position 13. In particular, it has now been found that the activity of the compounds can be improved upon by appropriate selection of certain highly specific ester groups at the 13 position, as specified below. In general, the compounds of the present invention tend to have a better pesticidal activity than do the compounds of the prior art, and many of the compounds of the present invention have a very substantially better activity. The compounds of the present invention are, in particular, substantially more active than those of the prior art, including U.S. Pat. No. 4,963,582, especially against fleas.